Abstract

Background

Model organisms have contributed substantially to our understanding of the etiology
of human disease as well as having assisted with the development of new treatment
modalities. The availability of the human, mouse and, most recently, the rat genome
sequences now permit the comprehensive investigation of the rodent orthologs of genes
associated with human disease. Here, we investigate whether human disease genes differ
significantly from their rodent orthologs with respect to their overall levels of
conservation and their rates of evolutionary change.

Results

Human disease genes are unevenly distributed among human chromosomes and are highly
represented (99.5%) among human-rodent ortholog sets. Differences are revealed in
evolutionary conservation and selection between different categories of human disease
genes. Although selection appears not to have greatly discriminated between disease
and non-disease genes, synonymous substitution rates are significantly higher for
disease genes. In neurological and malformation syndrome disease systems, associated
genes have evolved slowly whereas genes of the immune, hematological and pulmonary
disease systems have changed more rapidly. Amino-acid substitutions associated with
human inherited disease occur at sites that are more highly conserved than the average;
nevertheless, 15 substituting amino acids associated with human disease were identified
as wild-type amino acids in the rat. Rodent orthologs of human trinucleotide repeat-expansion
disease genes were found to contain substantially fewer of such repeats. Six human
genes that share the same characteristics as triplet repeat-expansion disease-associated
genes were identified; although four of these genes are expressed in the brain, none
is currently known to be associated with disease.

Conclusions

Most human disease genes have been retained in rodent genomes. Synonymous nucleotide
substitutions occur at a higher rate in disease genes, a finding that may reflect
increased mutation rates in the chromosomal regions in which disease genes are found.
Rodent orthologs associated with neurological function exhibit the greatest evolutionary
conservation; this suggests that rodent models of human neurological disease are likely
to most faithfully represent human disease processes. However, with regard to neurological
triplet repeat expansion-associated human disease genes, the contraction, relative
to human, of rodent trinucleotide repeats suggests that rodent loci may not achieve
a 'critical repeat threshold' necessary to undergo spontaneous pathological repeat
expansions. The identification of six genes in this study that have multiple characteristics
associated with repeat expansion-disease genes raises the possibility that not all
human loci capable of facilitating neurological disease by repeat expansion have as
yet been identified.